DESCRIPTION: (Investigator's abstract) The US. heart failure population numbers approximately 5 million and is growing. Despite treatment with current medical therapy, many patients remain symptomatic and require frequent hospitalization, placing an enormous burden on our health care system. Currently, the most ineffective arm of medical therapy are agents that modulate cardiac contractility. These agents improve patients' quality of life and decrease hospitalization rates, but have no effect on mortality rates. We propose to start development of a new class of cardiac contractility modulators acting directly on the force-producing cellular structure, the sarcomere. We will leverage Cytokinetics' robust high throughput screening technology to find compounds that modulate a reconstituted sarcomere. The ability to introduce a complex, well characterized, functional protein machine into a high throughput screen represents a significant advance in drug discovery. Using biochemical and physiological means, these compounds will be screened for secondary undesirable properties. This technology has already been validated against molecular motors that power mitosis. We expect to identify chemical compounds that have the potential to demonstrate proof of principle in relevant animal models. These compounds may eventually lead to a new class of contractility modulators that will play an important role in treating heart failure. PROPOSED COMMERCIAL APPLICATION: No new agents that modulate cardiac contractility have come on the market in nearly 10 years. The current market for digoxin, a 200 year old drug and the only one safe for chronic use in heart failure, is roughly $150 million per year (IMS data). The sales of non-generic dobutamine (Eli Lilly), used for acute heart failure, amounted to $86 million in 1998 (Paine Webber). Agents that directly target the force generating apparatus could be expected to be more effective and have fewer cellular toxicities. These properties may lead to improved patient outcomes. Naturally, such agents would gain a strong foothold in a large and growing marketplace.